The present invention relates to novel derivatives of prostaglandin compounds of the F-series (PGF), and more particularly to internal 1,15-lactones fluprostenol and related PGF analogs, and the use of such analogs for the treatment of increased intraocular pressure, such as that caused by glaucoma and the reduction of ocular hypertension.
The prostaglandins are a family of 20 carbon atom fatty acids, being structural derivatives of prostanoic acid, which exhibit useful activity in a wide variety of biological systems. Accordingly, prostaglandins represent useful pharmacological agents in the treatment and prevention of a wide variety of disease conditions. For a fuller discussion of prostaglandins and their uses, see Oates, et al., New England J. Med., Vol. 319, No. 11, pp. 689-698 and Vol. 319, No. 12, pp. 761-768 (1988) and the references cited therein.
Prostaglandin F2a (PGF2a) is a naturally-occurring prostaglandin which is widely manufactured and sold under a variety of trade names as an abortifacient, among other uses. See monograph 8065, page 1354 of The Merck Index, 12th edition (1996). It is also well known in the art that naturally-occurring prostaglandins can be topically applied to lower intraocular pressure. However, naturally-occurring prostaglandins generally cause inflammation and surface irritation of the eye.
Analogs of PGF2a which incorporate aromatic groups and other substituents into the omega chain have been prepared and found to be more potent and selective pharmacologic agents than the naturally-occurring compounds. An exemplary PGF2a analog of this type is fluprostenol, I6-(meta-trifluoromethylphenoxy)-17,18,19,20 tetranor PGF2a, and its pharmacologic profile is described in monograph 4231, page 711 of The Merck Index, 12th edition (1996). Unfortunately, the known synthetic analogs also produce the same undesirable side effects as the naturally-occurring compounds. There is, therefore, a need in the art for less inflammatory compounds for reducing intraocular pressure.
A number of simple PGF2a analog esters have been found to be potent and selective agents useful for the treatment of ocular hypertension. For example, latanoprost is the isopropyl ester of 13,14-dihydro-17-phenyl-18,19,20-trinor PGF2a and is widely marketed for the clinical treatment of glaucoma under the trade name Xalatan. See monograph 5387, page 918 of The Merck Index, 12th edition (1996). Likewise, the isopropyl ester of fluprostenol and of similar PGF2a analogs, such as cloprostenol, are specifically claimed as ocular antihypertensive agents in U.S. Pat. No. 5,665,773. The structures of naturally-occurring PGF2a (Structure I), fluprostenol (Structure II), and latanoprost (Structure III) are shown hereinbelow. For a review of these agents, see Linden and Aim, Drugs and Aging, Vol. 14, No. 5, pp. 387-398 (1999).

The esters of PGF2a and its analogs are believed to act as prodrugs in the eye, in that the ester form which is administered is hydrolyzed by endogenous ocular esterase enzymes, releasing the PGF2a analog free acid as the active pharmacologic agent. However, this also releases a toxic and irritant small aliphatic alcohol such as isopropanol or methanol into the eye. This potential side effect of the prostaglandin esters was recognized by L. Z. Bito in one of the earliest inventions which specified the use of these esters in the eye (see, U.S. Pat. No. 4,599,353). This irritant side effect has also been recognized more recently in the form of iridial melanocyte hyperplasia and hyperpigmentation which has been documented in patients treated with ophthalmic solutions of isopropyl esters such as Unoprostone (See page 2 of NDA 21-214 for Rescula™ Ciba Vision.)
In addition to the foregoing, the isopropyl esters of PGF2a analog compounds such as latanoprost and fluprostenol are highly viscous, glassy oils which are difficult to handle and to formulate into ophthalmic solutions. Worse yet, these compounds are prone to the retention of potentially toxic process solvents. There is, therefore, a need for a form of the prostaglandin analogs which is easier to handle and which does not release an irritant alcohol upon hydrolysis.
It is, therefore, an object of this invention to provide novel analogs of PGF2a that are useful for the reduction of intraocular pressure with less inflammation and toxic side effects than the naturally-occurring compounds and known analogs.
It is another object of this invention to provide novel analogs of PGF2a that preferably form orderly and high-melting crystals that can be easily handled and formulated into pharmaceutically-acceptable ophthalmic solutions.
It is also an object of this invention to provide novel ester analogs of PGF2a that do not release toxic irritants into the eye upon hydrolysis.